The objective of the proposed research is to further characterize the bone resorptive mediators which stimulate periapical bone destruction following infection of the dental pulp. A rat model will be employed in which pulpal and periapical destruction occurs with predictable kinetics after pulp exposure, permitting the definition of active (rapid) and chronic phases of destruction. Previous studies have implicated cytokines, in particular, interleukin 1 alpha (IL-1alpha), as key mediators in these events. Direct evidence for cytokine gene expression and synthesis in pulp and periapical lesions will be sought, using high sensitivity techniques for small tissue samples. These include polymerase chain reaction (PCR), in situ hybridization, and immunochemistry, in combination with cell identification techniques. Methods of specifically inhibiting the action of IL-1alpha, such as the use of antisense oligomers and an IL-1 receptor antagonist, will be explored. Finally, the general biologic role of inflammatory bone resorption will be explored in a resorption deficient rat model, in order to determine whether resorption is primarily destructive, or whether it may serve to protect the host against more severe consequences, including disseminated infection. These studies will provide definitive information on the mediators which stimulate resorption following infection of the pulp, and will permit the rational design of therapeutic agents which block resorption.